WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

• Published in: Acta neuropathologica communications 2014-12, Vol.2 (1), p.174-174, Article 174
• Main Authors: Zhukova, Nataliya, Ramaswamy, Vijay, Remke, Marc, Martin, Dianna C, Castelo-Branco, Pedro, Zhang, Cindy H, Fraser, Michael, Tse, Ken, Poon, Raymond, Shih, David J H, Baskin, Berivan, Ray, Peter N, Bouffet, Eric, Dirks, Peter, von Bueren, Andre O, Pfaff, Elke, Korshunov, Andrey, Jones, David T W, Northcott, Paul A, Kool, Marcel, Pugh, Trevor J, Pomeroy, Scott L, Cho, Yoon-Jae, Pietsch, Torsten, Gessi, Marco, Rutkowski, Stefan, Bognár, Laszlo, Cho, Byung-Kyu, Eberhart, Charles G, Conter, Cecile Faure, Fouladi, Maryam, French, Pim J, Grajkowska, Wieslawa A, Gupta, Nalin, Hauser, Peter, Jabado, Nada, Vasiljevic, Alexandre, Jung, Shin, Kim, Seung-Ki, Klekner, Almos, Kumabe, Toshihiro, Lach, Boleslaw, Leonard, Jeffrey R, Liau, Linda M, Massimi, Luca, Pollack, Ian F, Ra, Young Shin, Rubin, Joshua B, Van Meir, Erwin G, Wang, Kyu-Chang, Weiss, William A, Zitterbart, Karel, Bristow, Robert G, Alman, Benjamin, Hawkins, Cynthia E, Malkin, David, Clifford, Steven C, Pfister, Stefan M, Taylor, Michael D, Tabori, Uri
• Format: Article
• Language: English
• Subjects: Adolescent; beta Catenin - genetics; beta Catenin - metabolism; Care and treatment; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Cell Survival - radiation effects; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - mortality; Cerebellar Neoplasms - pathology; Cerebellar Neoplasms - radiotherapy; Child; Child, Preschool; Cohort Studies; Development and progression; Female; Genetic aspects; Humans; International Cooperation; Lithium - pharmacology; Male; Medulloblastoma; Medulloblastoma - genetics; Medulloblastoma - mortality; Medulloblastoma - pathology; Medulloblastoma - radiotherapy; Mutation - genetics; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - radiation effects; Radiotherapy - adverse effects; Stem cells; Transplantation; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Wnt Proteins - metabolism; Wnt Signaling Pathway - drug effects; Young Adult
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-014-0174-y

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p